Analysis of interspecific somatic cell hybrids segregating human chromosomes permits the localization of human genes to specific chromosomes. We have previously constructed a large panel of human-rodent hybrids and used them to chromosomally map protooncogenes and various other human genes by Southern analysis of hybrid cell DNAs with cloned DNA probes. In collaborative studies, these hybrids have now been used to chromosomally map several additional proto-oncogenes and putative chromosomal neoplastic breakpoints, multiple tRNA and cytochrome P450 genes, and a variety of genes for regulatory, structural, and enzyme proteins. Current techniques allow construction of genomic restriction maps of genes and pseudogenes and usually permit assessment of copy number. The probes are simultaneously used to identify restriction fragment length polymorphism (RFLPs) in DNAs from normal individuals; these RFLPs are used in subsequent mapping studies by genetic linkage analysis and this is a major portion of the current research effort. In collaborative studies with the B. D. Weintraub lab, close linkage has been found between the syndrome of generalized thyroid hormone resistance (GTHR) and the human c- erbA beta gene indicating that a defect in this thyroid hormone receptor probably underlies the disease in some cases. Other collaborative studies have established linkage of the MENl (multiple endocrine neoplasia, type 1) disease gene to the INT 2 locus on chromosome 11q13. In studies designed to detect the involvement of beta-polymerase or Poly (ADPribose) polymerase in diseases associated with DNA repair defects, no abnormalities of these genes have been found in xeroderma pigmentosum and ataxia telangiectasia by Southern and Northern analyses. The use of a more discriminating RNase protection assay have been unsuccessful and a genetic approach will probably be required.